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Mechanisms of suppression by suppressor T cells

Nature Immunology volume 6, pages 338–344 (2005)Cite this article

Abstract

Mechanisms of immunosuppression by CD4+CD25+ suppressor T cells have been addressed using many in vitro and in vivo conditions. However, those studies have not yielded a single mode of action. This review will discuss the mechanisms of suppression, which include the local secretion of cytokines such as TGF-β and direct cell contact through binding of cell surface molecules such as CTLA-4 on suppressor T cells to CD80 and CD86 molecules on effector T cells. Suppression requires the appropriate colocalization of suppressor and effector T cells in different tissue and may involve the interference with T cell receptor signaling that triggers transcription factors important in regulating effector cell function.

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Figure 1: CTLA-4 and CD80 and/or CD86 in suppression.
Figure 2: Making effector T cells insensitive to suppression.
Figure 3: TGF-β in the suppression of CD8 T cells.

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References

  1. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).

    CAS  PubMed  Google Scholar 

  2. Fontenot, J.D. and Rudensky, A. A well adapted regulatory contrivance: regulatory T cell development and the Forkhead family transcription factor Foxp3. Nat. Immunol. 6, 338–344 (2005).

    Article  Google Scholar 

  3. Jordan, M.S., Riley, M.P., von Boehmer, H. & Caton, A.J. Anergy and suppression regulate CD4+ T cell responses to a self peptide. Eur. J. Immunol. 30, 136–144 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Jordan, M.S. et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2, 301–306 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Walker, L.S., Chodos, A., Eggena, M., Dooms, H. & Abbas, A.K. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J. Exp. Med. 198, 249–258 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Apostolou, I., Sarukhan, A., Klein, L. & von Boehmer, H. Origin of regulatory T cells with known specificity for antigen. Nat. Immunol. 3, 756–763 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Gotter, J. & Kyewski, B. Regulating self-tolerance by deregulating gene expression. Curr. Opin. Immunol. 16, 741–745 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Hsieh, C.S. et al. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21, 267–277 (2004).

    Article  CAS  PubMed  Google Scholar 

  9. Apostolou, I. & Von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Chen, T.C., Waldmann, H. & Fairchild, P.J. Induction of dominant transplantation tolerance by an altered peptide ligand of the male antigen Dby. J. Clin. Invest. 113, 1754–1762 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mahnke, K., Qian, Y., Knop, J. & Enk, A.H. Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells. Blood 101, 4862–4869 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Thorstenson, K.M. & Khoruts, A. Generation of anergic and potentially immunoregulatory CD25+CD4 T cells in vivo after induction of peripheral tolerance with intravenous or oral antigen. J. Immunol. 167, 188–195 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Khattri, R., Cox, T., Yasayko, S.A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003).

    Article  CAS  PubMed  Google Scholar 

  14. Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Buer, J. et al. Interleukin 10 secretion and impaired effector function of major histocompatibility complex class II-restricted T cells anergized in vivo. J. Exp. Med. 187, 177–183 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. O'Garra, A. & Vieira, P. Regulatory T cells and mechanisms of immune system control. Nat. Med. 10, 801–805 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Hu, D. et al. Analysis of regulatory CD8 T cells in Qa-1-deficient mice. Nat. Immunol. 5, 516–523 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Sakaguchi, N. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunologic tolerance to self and non-self. Nat. Immunol. 6, 345–352 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Belkaid, Y. & Rouse, B.T. Natural T regulatory cells in infectious disease. Nat. Immunol. 6, 353–360 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Shevach, E.M. CD4+ CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2, 389–400 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Nakamura, K., Kitani, A. & Strober, W. Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor β. J. Exp. Med. 194, 629–644 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Thornton, A.M., Piccirillo, C.A. & Shevach, E.M. Activation requirements for the induction of CD4+CD25+ T cell suppressor function. Eur. J. Immunol. 34, 366–376 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. de la Rosa, M., Rutz, S., Dorninger, H. & Scheffold, A. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur. J. Immunol. 34, 2480–2488 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Taylor, P.A. et al. B7 expression on T cells down-regulates immune responses through CTLA-4 ligation via T-T interactions. J. Immunol. 172, 34–39 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Paust, S., Lu, L., McCarty, N. & Cantor, H. Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc. Natl. Acad. Sci. USA 101, 10398–10403 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mellor, A.L. & Munn, D.H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762–774 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Grossman, W.J. et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21, 589–601 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Pasare, C. & Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033–1036 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. McHugh, R.S. et al. CD4+CD25+ immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16, 311–323 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y. & Sakaguchi, S. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat. Immunol. 3, 135–142 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Stephens, G.L. et al. Engagement of glucocorticoid-induced TNFR family-related receptor on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J. Immunol. 173, 5008–5020 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Tone, M. et al. Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc. Natl. Acad. Sci. USA 100, 15059–15064 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Klein, L., Khazaie, K. & von Boehmer, H. In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc. Natl. Acad. Sci. USA 100, 8886–8891 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fisson, S. et al. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J. Exp. Med. 198, 737–746 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yamazaki, S. et al. Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J. Exp. Med. 198, 235–247 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. von Boehmer, H. Dynamics of suppressor T cells: in vivo veritas. J. Exp. Med. 198, 845–849 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tang, Q. et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J. Exp. Med. 199, 1455–1465 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tarbell, K.V., Yamazaki, S., Olson, K., Toy, P. & Steinman, R.M. CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J. Exp. Med. 199, 1467–1477 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jaeckel, E., von Boehmer, H. & Manns, M. Antigen-specific Foxp3 transduced T cells can control established Type 1 diabetes. Diabetes 54, 306–310 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. von Boehmer, H. Type 1 diabetes: focus on prevention. Nat. Med. 10, 783–784 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Sarween, N. et al. CD4+CD25+ cells controlling a pathogenic CD4 response inhibit cytokine differentiation, CXCR-3 expression, and tissue invasion. J. Immunol. 173, 2942–2951 (2004).

    Article  CAS  PubMed  Google Scholar 

  44. Huehn, J. et al. Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells. J. Exp. Med. 199, 303–313 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mottet, C., Uhlig, H.H. & Powrie, F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J. Immunol. 170, 3939–3943 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Jonuleit, H. et al. Infectious tolerance: human CD25+ regulatory T cells convey suppressor activity to conventional CD4+ T helper cells. J. Exp. Med. 196, 255–260 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Schorle, H., Holtschke, T., Hunig, T., Schimpl, A. & Horak, I. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352, 621–624 (1991).

    Article  CAS  PubMed  Google Scholar 

  48. Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).

    Article  CAS  PubMed  Google Scholar 

  49. Malek, T.R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Van Parijs, L. & Abbas, A.K. Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science 280, 243–248 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Wolf, M., Schimpl, A. & Hunig, T. Control of T cell hyperactivation in IL-2-deficient mice by CD4+CD25− and CD4+CD25+ T cells: evidence for two distinct regulatory mechanisms. Eur. J. Immunol. 31, 1637–1645 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Almeida, A.R., Legrand, N., Papiernik, M. & Freitas, A.A. Homeostasis of peripheral CD4+ T cells: IL-2Rα and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J. Immunol. 169, 4850–4860 (2002).

    Article  PubMed  Google Scholar 

  53. Furtado, G.C., Curotto de Lafaille, M.A., Kutchukhidze, N. & Lafaille, J.J. Interleukin 2 signaling is required for CD4+ regulatory T cell function. J. Exp. Med. 196, 851–857 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Malek, T.R. & Bayer, A.L. Tolerance, not immunity, crucially depends on IL-2. Nat. Rev. Immunol. 4, 665–674 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Bachmann, M.F., Kohler, G., Ecabert, B., Mak, T.W. & Kopf, M. Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous. J. Immunol. 163, 1128–1131 (1999).

    CAS  PubMed  Google Scholar 

  56. Bachmann, M.F. et al. Normal pathogen-specific immune responses mounted by CTLA-4-deficient T cells: a paradigm reconsidered. Eur. J. Immunol. 31, 450–458 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Bacchetta, R. et al. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J. Exp. Med. 179, 493–502 (1994).

    Article  CAS  PubMed  Google Scholar 

  58. Van Parijs, L. et al. Functional responses and apoptosis of CD25 (IL-2R α)-deficient T cells expressing a transgenic antigen receptor. J. Immunol. 158, 3738–3745 (1997).

    CAS  PubMed  Google Scholar 

  59. Sundstedt, A., O'Neill, E.J., Nicolson, K.S. & Wraith, D.C. Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J. Immunol. 170, 1240–1248 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Vieira, P.L. et al. IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J. Immunol. 172, 5986–5993 (2004).

    Article  CAS  PubMed  Google Scholar 

  61. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

    Article  CAS  PubMed  Google Scholar 

  62. Barrat, F.J. et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J. Exp. Med. 195, 603–616 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Annacker, O. et al. CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J. Immunol. 166, 3008–3018 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. Asseman, C., Mauze, S., Leach, M.W., Coffman, R.L. & Powrie, F. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J. Exp. Med. 190, 995–1004 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Suri-Payer, E. & Cantor, H. Differential cytokine requirements for regulation of autoimmune gastritis and colitis by CD4+CD25+ T cells. J. Autoimmun. 16, 115–123 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Green, E.A., Gorelik, L., McGregor, C.M., Tran, E.H. & Flavell, R.A. CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-β-TGF-β receptor interactions in type 1 diabetes. Proc. Natl. Acad. Sci. USA 100, 10878–10883 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chen, M.L. et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-β signals in vivo. Proc. Natl. Acad. Sci. USA 102, 419–424 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. Lin, C.Y., Graca, L., Cobbold, S.P. & Waldmann, H. Dominant transplantation tolerance impairs CD8+ T cell function but not expansion. Nat. Immunol. 3, 1208–1213 (2002).

    Article  CAS  PubMed  Google Scholar 

  69. Piccirillo, C.A. & Shevach, E.M. Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J. Immunol. 167, 1137–1140 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Huber, S. et al. Cutting edge: TGF-β signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J. Immunol. 173, 6526–6531 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Suvas, S., Kumaraguru, U., Pack, C.D., Lee, S. & Rouse, B.T. CD4+CD25+ T cells regulate virus-specific primary and memory CD8+ T cell responses. J. Exp. Med. 198, 889–901 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Onizuka, S. et al. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody. Cancer Res. 59, 3128–3133 (1999).

    CAS  PubMed  Google Scholar 

  73. Yang, Y., Huang, C.T., Huang, X. & Pardoll, D.M. Persistent Toll-like receptor signals are required for reversal of regulatory T cell-mediated CD8 tolerance. Nat. Immunol. 5, 508–515 (2004).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The help of L. Benson and L. von Boehmer in preparing this manuscript is acknowledged. Supported by the National Institutes of Health (R37AI51378).

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    Harald von Boehmer

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von Boehmer, H. Mechanisms of suppression by suppressor T cells. Nat Immunol 6, 338–344 (2005). https://doi.org/10.1038/ni1180

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